Clinical profiles and prognosis of acute heart failure in adult patients with dystrophinopathies on home mechanical ventilation.

AIMS: Duchenne muscular dystrophy (DMD) is characterized by respiratory and heart involvements. In the context of permanently wheelchair bound and on mechanical ventilation (MV) patients, the clinical presentation of acute heart failure (AHF) syndrome may be atypical. We sought to describe clinical and genetic profiles and to determine prognosis of DMD and Becker muscular dystrophy (BMD) patients on home MV (HMV), hospitalized for AHF. METHODS AND
RESULTS: We included genetically proven DMD and BMD patients on HMV admitted for AHF. A total of 13 patients (11 DMD and 2 BMD) fulfilled the inclusion criteria. Median age was 34.0 [interquartile range (IQR) 26.0; 40.0] years. Median pulmonary vital capacity was 9.0% (6.0; 15.0) of predicted value. Long-term invasive ventilation was performed in 69% of patients. All the 11 DMD patients carried out-of-frame DMD gene mutations. At admission, dyspnoea was present in 46%, lipothymia in 23%, and abdominal discomfort in 38.4% of patients. A total of 53.8% of patients showed anasarca. Cardiogenic shock presentation was found in six patients (46%). Ejection fraction was severely altered [median 25% (IQR 20; 30)]. Intra-hospital mortality rate was 30%, reaching 53.8 % after 1 year. Previous episodes of AHF ≥ 2 were associated with intra-hospital mortality (P = 0.025). In patients with cardiogenic shock, intra-hospital mortality rate was 66.6%, reaching 83.3% after 1 year.
CONCLUSIONS: In adult DMD and BMD patients with severe ejection fraction alteration and on HMV, admitted for AHF, right cardiac signs are frequent. The intra-hospital and 1 year mortality rate was high and was associated with previous episodes of AHF ≥ 2.

Introduction

Duchenne muscular dystrophy (DMD) is an X‐linked recessive genetic disorder, caused by mutations in the DMD gene and affects 1 of 3500 male births.1 The DMD gene is the largest gene known in humans (2.3Mb of genomic DNA). Depending on the presence or the absence of the translational reading frame, mutations in the DMD gene lead to DMD in case of out frame mutations. Conversely, the milder form, Becker muscular dystrophy (BMD), results from in‐frame DMD mutations.2, 3, 4 In DMD, the underlying gene mutations cause the absence of dystrophin, a protein located on the inner side of the skeletal and the cardiac muscle cells, linking the internal cytoskeleton to the extracellular matrix.5 Beside the functional limitation due to the involvement of the skeletal muscles, respiratory and cardiac muscles involvements in DMD patients had the main impact on the life expectancy. Over the last few decades, the possibility to support the pulmonary function with mechanical ventilation has radically improved the survival of DMD patients.6, 7 In the meantime, the support of this vital function has allowed the clinical emergence of advanced cases of heart failure. In this context of severely affected patients, usually wheelchair bound and on mechanical ventilation, the clinical presentation of acute heart failure (AHF) syndrome may be atypical and the assessment of its severity a difficult task. Some of these patients are admitted to Intensive Care Unit (ICU), but clinical pictures and outcomes of such patients are poorly reported. In this study, we sought (i) to describe clinical profiles and genetic pattern and (ii) to determine intra‐hospital mortality rate and 1 year mortality rate of patients with DMD and BMD on home mechanical ventilation (HMV), hospitalized in ICU for AHF.

Materials and methods

Study setting

The ICU of the Raymond Poincaré University Hospital is a reference centre that specializes in respiratory and cardiac management of neuromuscular disorders at advanced stages. In this unit, neuromuscular patients are followed on annual basis in a multidisciplinary consultation that includes cardiac and pulmonary assessment in the home ventilation unit because of restrictive respiratory failure.

Study design

Since 2006–16, a total of 137 admissions of patients suffering from dystrophinopathies (DMD and BMD) were notified into this unit. For the present study, we included genetically proven DMD and BMD patients on HMV because of significant chronic respiratory insufficiency and with chronic cardiomyopathy and admitted in the ICU of the Raymond Poincaré University Hospital for AHF.

We retrospectively reviewed the medical records of these patients and collected clinical setting, electrocardiogram data, left ventricular ejection fraction (EF) from echocardiography, B‐type natriuretic peptide, and blood creatinine level from blood results at admission, intra‐hospital mortality, and mortality within 1 year. Doppler echocardiographies were performed by the same experienced cardiologist (A.F.) with a Siemens CV70 device (ACUSON), according to the guidelines issued by the American Society of Echocardiography. Spirometry variables and lung volumes were routinely measured using a Vmax 229 SensorMedics System (Yorba Linda, CA, USA) according to standard guidelines.

The study was performed in compliance with the ethical principles formulated in the declaration of Helsinki and was approved by the French regulatory board (Commission Nationale de l'Informatique et des Libertés). The study was registered in ClinicalTrials.gov (identifier: NCT02685215 ).

Clinical definitions

AHF is defined as a gradual or rapid change in heart failure signs and symptoms requiring urgent therapy.8 Cardiogenic shock is a life‐threatening emergency and is defined by persistent hypotension and tissue hypoperfusion due to cardiac dysfunction in the presence of adequate intravascular volume and left ventricular filling pressure.

Genetic analysis

Semi‐quantitative fluorescent multiplex PCR using genomic DNA was performed for detecting deletions and duplications.9 Other types of mutations were detected by sequencing all DMD gene exons or by the analysis of muscle dystrophin mRNA (reverse transcription (RT)–PCR).9 For each patient, we recorded the mutation type and the involved gene exons. The dystrophin protein contains several functional domains, including the N‐terminal, the rod domain, the cysteine‐rich domain, and the C‐terminal. The rod domain is composed of three subdomains separated by four hinges (H1, H2, H3, and H4), subdomains that we respectively indicated as H3 in Table 1. For each patient, we determined the most distal dystrophin domain theoretically involved by the DMD gene mutation and beyond that which the protein is truncated if any dystrophin is produced. Therefore, the more distal is the mutation, less are the affected domains if any residual dystrophin is synthesized. For instance, out‐of‐frame mutations involving the N‐terminal affect theoretically all the dystrophin domains while out‐of‐frame mutations involving the C‐terminal spare the N‐terminal and the entire rod domain.

Table 1

Genetic, clinical profiles, and mortality of patients with Duchenne muscular dystrophy

Patient's characteristics			VC (%)/invasive or non‐invasive HMV/HMV duration	Cardiac history			AHF characteristics
Patient no./phenotype/age (years)	DMD gene mutation	More distally involved dystrophin domain		Previous AHF episodes: yes or no (number)	EF (%)/EKG	Cardiac drugs	Clinical presentation of AHF	BNP (pg/mL)	Creat (μmol/L)	AHF drug management	Outcome
1/DMD/26	c.141dup, p.Arg48GlufsX41	N‐terminal	8/I/24/24 h	Yes (n = 3)	15/RBBB	ACEI, BB, D, MRA, digoxin	AD, lipothymia, ascites, BP 60/30, pleural effusion	—	33	Inotropes	IH death
2/DMD/23	Del exon 46–52	Rod domain [H2–H3]	22/NI/10/24 h	Yes (n = 1)	29/LBBB	ACEI, BB, D	Dyspnoea, BP 90/40	1199	<20	MT	Death < 1 y
3/DMD/31	c.4231C > T, p.Gln1411X	Rod domain [H2–H3]	10/I/24/24 h	Yes (n = 4)	20/LBBB	ACEI, BB, D	Dyspnoea, BP 70/30, sepsis	>5000	<20	Inotropes, vasopressors	IH death
4/DMD/38	Dup exon 3–7	N‐terminal	15/I/24/24 h	Yes (n = 1)	15/RBBB	ACEI, BB, D	Leg oedema, anasarca, BP 120/80	334	<20	MT	Death < 1 y
5/DMD/38	c.5602_5605delAGAA, p.Arg1868GlufsX5	Rod domain [H2–H3]	6/I/24/24 h	Yes (n = 1)	20/LBBB	ACEI, BB, D, MRA	Leg oedema, anasarca, SBP 77/42, pulmonary congestion	—	31	MT	Survival
6/DMD/34	Del exon 50–52	Rod domain [H2–H3]	5/I/24/24 h	Yes (n = 1)	30/LBBB	ACEI, BB, D	Leg oedema, AD, ascites, BP 90/60	—	—	MT, CRT	Survival
7/DMD/26	Del exon 8–13	N‐terminal	12/I/24/24 h	Yes (n = 1)	20/Normal	ACEI, BB	AD, leg oedema, ascites, BP 70/30, pleural effusion	—	—	Inotropes	Death < 1 y
8/DMD/20	Del exon 52–79	Rod domain [>H3]	32/NI/10/24 h	No	20/LBBB	ACEI, BB, D	Dyspnoea, BP 80/40, pleural effusion	2370	36	MT	IH death
9/DMD/27	Dup exon 44–49	Rod domain [H2–H3]	9/I/24/24 h	Yes (n = 1)	45/RBBB	ACEI, BB	Leg oedema, BP 95/45, sepsis	466	30	MT, dialysis	Survival
10/DMD/40	Del exon 8–9	N‐terminal	6/NI/10/24 h	No	35/RBBB	ACEI, BB, D	Dyspnoea, sepsis, BP 116/92	—	—	MT	Survival
11/BMD/49	Dup exon 14–47	Rod domain [<H2]	5/I/24/24 h	Yes (2)	30/LBBB	ACEI, BB, D	Leg oedema, ascite, anasarca, pleural effusion, BP 75/50	362	42	Inotropes, vasopressors, dialysis	IH death
12/BMD/49	c.94 − 1G > T	N‐terminal	23/NI/8/24 h	No	25/LBBB	ACEI, BB, D	Dyspnoea, BP 120/80	—	—	MT, CRT‐D	Survival
13/DMD/45	Del exon 45–50	Rod domain [H2–H3]	1/I/24/24 h	No	30/LBBB	ACEI	Lipothymia, Dyspnoea, BP 80/49	(Nt‐pro BNP 12000)	33	Inotropes	Survival

ACEI, angiotensin‐converting enzyme inhibitor; AD, abdominal discomfort; BB, beta‐blocker; BNP, B‐type natriuretic peptide; BP, blood pressure in mmHg; Creat, creatinine level in blood; CRT‐D, cardiac resynchronization therapy + defibrillator; D, loop diuretic; De, deletion; Dup, duplication; EF, left ventricular ejection fraction (%); HMV, home mechanical ventilation; I, invasive ventilation; IH, intra‐hospital; LBBB, left bundle branch block; MRA, mineralocorticoid receptor antagonist; MT, medical therapy; MV, mechanical ventilation; N, normal; NI, non‐invasive ventilation; RBBB, right bundle branch block; y, years.

Statistics

Continuous variables were described by median ± interquartile range (IQR) and compared by Wilcoxon test; dichotomous or categorical variables were described by number of subjects and percentage and compared by Fisher's exact test. Statistical analysis was performed using R® (http://www.R-project.org/).

Results

Study population (Table 1)

Among the 137 admitted patients, 13 (11 DMD and 2 BMD) fulfilled the inclusion criteria of our study. Median age was 34.0 (IQR 26.0; 40.0) years. At baseline, all patients were wheelchair bound and disclosed chronic restrictive respiratory failure needing HMV. The two BMD patients (nos. 11 and 12) respectively lost ambulation at 23 and 19 years old, thus falling into the severe BMD spectrum. Gastrostomy was present in four patients out of 13 (30.7%). Median pulmonary vital capacity was 9.0% (6.0; 15.0) of predicted value. Long‐term invasive ventilation was performed in nine of 13 patients (69%). Eleven patients were already treated with angiotensin‐converting enzyme inhibitors (ACEI), 11 with beta‐blockers and 10 with diuretics. Eight patients had previous hospitalizations for AHF; among them, three patients had ≥2 episodes of previous hospitalization for AHF. Two patients had an elevation of liver transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2‐fold the upper limit of the normal range), and six patients showed a >2‐fold elevation of the gamma‐glutamyl transpeptidase.

Genetic results

Genetic results regarding the 13 patients are shown in Table 1. Mutations in the DMD gene were identified in all the 13 patients. The two BMD patients (nos. 11 and 12) carried respectively an in‐frame large duplication of exons 14–47 and intron 2 acceptor splice site mutation (c.94 − 1G > T) that probably lead to in‐frame exon skipping. Unfortunately, no muscle biopsy was available for mRNA analysis in this latter patient. However, muscle mRNA analysis in another patient carrying the same intronic mutation clearly showed exon 3 skipping at the mRNA level making this skipping likely in patient 12. In all the 11 remaining DMD patients, we identified out‐of‐frame mutations including large exonic deletions (six patients) and duplications (three patients), one nucleotide insertion in exon 3 (one patient), four nucleotides deletion in exon 40 (one patient), and a premature stop codon in exon 30 (one patient). The exons 52–79 deletion found in patient 8 encompassed the DMD gene and involved contiguous genes (at least NR0B1 and GK genes) resulting in mental retardation, congenital adrenal hypoplasia, and glycerol kinase deficiency. Five of these mutations involved all the dystrophin domains from the N‐terminal domain (patients 1, 4, 7, 10, and 12), one spared the N‐terminal domain (patient 11), six spared the N‐terminal and